Preparation of vitamin a aldehyde



United States Patent PREPARATION OF VITAMIN A ALDEHYDE Howard C. Klein,Brooklyn, N. Y., assignor to Nopco Chemical Company, Harrison, N. .L, acorporation of New Jersey No Drawing. Application August 21, 1957 SerialNo. 679,518

Claims. (Cl. 260-563) This invention relates to the preparation ofvitamin A and more specifically, relates to the preparation ofintermediate compounds which can be employed in the preparation ofvitamin A.

The synthesis of vitamin Ahas engaged the attention of the art since thestructure of vitamin A was first disclosed by Karrer in 1933. Manyroutes for the synthesis of vitamin A have been advanced and aconsiderable body of literature has developed concerning the preparationof vitamin A, vitamin A active materials and vitamin A intermediates.Because of the demand for vitamin A and the market which exists for thiscompound, eiforts are constantly being made to devise new and improvedmethods, both for the total synthesis of vitamin A and for thepreparation of intermediate compounds which can be employed in theproduction of vitamin A.

For instance, in U. S. patent applications, Serial No. 545,123 of Klein,Beckmann and Schaaf, filed November 4, 1955, now Patent No. 2,819,310,and Serial No. 545,- 125 of Schaaf, Klein and Kapp, filed November 4,1955, now Patent No. 2,819,308, methods have been disclosed for thepreparation of vitamin A active material by treating either the cis orthe trans form of a material having the empirical formula C H O and astructural formula which compound contains the beta ionone ringstructure, four ethylenic bonds and one hydroxyl group, and which in thetrans configuration has an absorption maximum in the ultra-violet of2710 A., a molecular extinction coefficient at that wave length of29,100 and has a refractive index at 20 C. of 1.552 and which in the cisconfiguration has an absorption maximum in the ultra-violet at 2740 A.,a molecular extinction coefficient at that wave length of 25,900 and hasa refractive index at 16 C. of 1.535 (referred to hereinafter asCompound I) with a boron trifiuoride hexamethylene tetramine complexunder appropriate reaction conditions in a water-containing aromatichydrocarbon solvent solution or in solution in a solvent selected fromthe group consisting of acetone, acetonitrile, acrylonitrile, benzylcyanide, dioxane, isopropenyl acetate and tetrahydrofuran. Thereafter,the reaction mixture is worked up with an alkaline material followed byextraction with an appropriate solvent, e. g., hexane, ether, etc. Theresulting product which is vitamin A active is referred to hereinafteras Compound IV. Compound IV contains a hexamethylene tetramine fragmentin the molecule.

Compound IV when tested biologically "onrats shows a vitamin A activityof about 50%. Its ultra-violet spectrographic characteristics arepractically identical 2,862,030 Patented Nov. 25, 1958 with those ofvitamin A; however, infra-red spectrographic analysis shows thatCompound IV does not contain a hydroxyl group, but that it does containan amine group. Analysis of Compound IV by the Kjeldahl method showsthat Compound IV has a nitrogen content which is about 9.6% and is abouttwice the nitrogen content of vitamin A amine. Vitamin A amine has thesame structure as vitamin A, only the amine group has replaced thehydroxyl group of vitamin A. The 9.6% figure is also twice as large asthe basic nitrogen value which is obtained by titration of this compoundwith approximately 0.02 N perchloric acid in glacial acetic acid. Thisindicates that the molecule contains more than one nitrogen atom andthat not all of it is basic. Thus the physical and chemicalcharacteristics of Compound IV indicate that it contains the vitamin Achromophoric system wherein the hydroxyl group of vitamin A has beenreplaced by a basic fragment similar to a major portion of thehexamethylene tetramine molecule.

Compound IV is a viscous liquid soluble in ethyl ether, ethyl alcohol,acetone and similar solvents. It has an absorption maximum in theultra-violet region of the spectrum at 3250 A. and has at that wavelength an extinction coefiicient of about 1000. If it is treated withhydrobromic acid, a product is obtained which has an absorption maximumat 3300 A. Likewise treatment of Compound IV with phosphoric acid givesa product having an absorption maximum at 3280-3300 A. Presumably salts:of Compound IV are formed by treatment with hydrobromic acid andphosphoric acid since treatment of the products with alkali gives ineach case the original Compound IV. Acetylation of Compound IV withacetic anhydride gives a product which when analyzed by infraredanalysis shows the presence of an amide band in the infraredspectrographic curve.

Compound IV can be converted to vitamin A :amine by treating it withaluminum isopropoxide in accordance with the procedure disclosed andclaimed in U. S. patent application Serial No. 545,124, Klein, filedNovember 4, 1955, now Patent No. 2,819,309. Also Compound IV can beconverted into vitamin A aldehyde by treating it with iodine inaccordance with the procedure disclosed and claimed in U. S. patentapplication, Serial No. 545,122, Klein and Grassetti, filed November 4,1955, now Patent No. 2,819,311.

However, Compound IV has some disadvantages regarding its use as astarting material for producing vitamin A aldehyde by treatment withiodine. For instance, to obtain Compound IV, the reaction mixtureobtained from the reaction between Compound I and borontrifluoridehexamethylene tetramine complex must be worked up by treatment with analkaline material, e. g., sodium hydroxide, ammonia, ethanolamine, etc.,in order to react with all of the boron trifluoride present in thereaction mixture. Thereafter Compound IV is recovered from the reactionmixture by extraction with a solvent followed by evaporation to removethe solvent. The extraction step for recovering the worked up reactionproduct involves the use of solvents which are both hazardous andexpensive thereby. requiring safety precautions as well as recoveryoperations. The evaporation step involves careful control owing to thesensitivity of Compound IV to heat and oxidation. 7

Accordingly, it is an object of the present invention to provide animproved method for the synthesis of vitamin A. y H

It is a more particular object of this invention to pro vide a novel andeffective method for the production of 3 valuable intermediates usefulin the production of vitamin A.

A further object is the preparation of vitamin A aldehyde in a moredirect and convenient manner than has heretofore been accomplished.

.A specific object is. the preparation of vitamin A aldehyde inincreased yields from Compound I and free from the presence of anhydrovitamin A.

Further objects will become apparent from the detailed description givenhereinaften. It is intended, however, that the detailed description andthe specific examples donot limit the invention but merely indicate thepreferred embodiments of the invention since various changes andmodifications within the scope thereof willbecome apparent to thoseskilled in the art.

It has been discovered that the above and other objectscan be achievedby treating with iodine, preferably in the presence of water, thereaction product of Compound I and boron trifluoride hexamethylenetetramine complex. Preferably the reaction product need not beisolated,- but may be treated with iodine in situ in its reactionmixture. In this manner, the hitherto essential steps of working up thereaction product with alkaline tained in a manner similar to theprocedures described in U. S. patent applications Serial No. 545,123 andSerial No. 545,125, referred to above. The cis or the trans form ofCompound I may be reacted with the aforesaid boron trifluoridehexamethylene tetramine complex in a water-containing aromatichydrocarbon solution, such as benzene, toluene, xylene, methyl isopropylbenzene, isopropyl benzene, ethyl benzene, diethyl benzene, mesitylene,butyl benzene, amyl benzene. Similar aromatic hydrocarbon solvents arehighly suitably as the reaction medium. These hydrocarbon solvents aresubstantially water-immiscible but they will dissolve a small percentageof water. Also acrylonitrile, benzyl cyanide, isopropenyl acetate andtetrahydrofuran may be used. When this reaction product, withoutisolating it from its reaction mixture, is to be subsequently treatedwith iodine, preferably in the presence of water to effect itsconversion to vitamin A aldehyde, it is highly preferable to select asolvent that will form a homogeneous system. Examples of suitablesolvents are acetone, acetonitrile, dioxane, and-mixtures of suchsolvents. The preferred solvent is dioxane containing a small amount ofwater.

The hexamethylene tetramine complex of boron trifiuoridc which isemployed is one in which the ratio of boron trifiuoride to hexamethylenetetramine varies from an average of about 1.5 to an average of about 2.5molecules of boron trifluoride for each molecule of hexamethylenetetramine. Complexes containing larger or smaller ratios of borontrifluoride are not nearly as satisfactory for use in our process ascomplexes containing these preferred ratios. Preferably a complexcontaining an average of about 2 molecules of boron trifluoride for eachmolecule of hexamethylene tetramine is employed. In the reaction theboron trifluoride complex does not act in the normal catalytic sense. Inorder to obtain the most satisfactory results when using a complexcontaining about 2 molecules of boron trifluoride for each molecule ofhexamethylene tetramine, it is necessary that the boron trifluoridehexamethylene tetramine complex be employed in at least about a mole tomole ratio in proportion to the amount of Compound I which is used inthe reaction. Although ratios of less than one to one will produce someproduct, by far the best results are obtained when at least about a oneto one ratio is employed. Molar ratios greater than one to one can beused and are preferred, e. g., two moles of boron trifluoride tetraminecomplex to one mole of Compound I. When the ratio of boron trifluorideto hexamethylene tetramine in the complex is decreased, the mole ratioof the complex to Compound I is preferably increased a correspondingamount. Also when the ratio of boron trifluoride to hexamethylenetetramine in the complex is increased, the mole ratio of the complex toCompound I can be correspondingly decreased, if desired, although it isnot necessary to do so.

It is preferred that the reaction be carried out in an inert atmosphereuch as an atmosphere of nitrogen, helium or some other inert gas.

The temperature at which the reaction is carried out can be varied.Preferably, however, the temperature should be between about roomtemperature and about 35 C.; however, if desired, either lower or highertemperatures can be employed. We have found that at room temperature thereaction will normally proceed to completion in not more than aboutthree hours and in many instances will proceed to completion in fromfifteen to thirty minutes.

- As pointed out above, the preferred solvent is dioxane containing asmall amount of water. Since water forms a complex with borontrifluoride, it might be thought that the presence of water in thereaction mixture would inactivate the boron trifiuoride hexamethylenetetramine complex. However, water does not inactivate the borontrifluoride hexamethylene complex. Preferably when dioxane is thesolvent, water is added to the reaction mix ture to increase thepolarity of the solvent since the reaction appears to proceed moreefliciently in a highly polar solvent. Thus, from about 1% to 10% ofWater based upon the volume of the dioxane is preferably employed. Also,if desired, water can be used in the reaction medium when solvents otherthan dioxane are employed.

Preferably rather dilute solutions of Compound I are employed incarrying out the reaction of Compound I and boron trifluoridehexamethylene tetramine complex. In most cases a concentration of from0.1 gram to about 1.0 gram of Compound I is present for each ml. oftotal solution.

The resulting product which is a new complex produced by interaction ofCompound I and boron trifluoride hexamethylene tetramine complex asdescribed in U. S. patent application Serial No. 679,519 of Grassettifiled concurrently herewith has been isolated and is a practicallycolorless solid, tends to decompose and has a sintering point at aboutC. It has a X max=3300 A. and an If instead of isolating this product,it is worked up by treatment with an alkaline material as described inU.-S. patent application Serial No. 545,123, Klein, Beckmann and Schaaffiled November 4, 1955, or Serial No. 545,125, Schaaf, Klein and Kappfiled November 4, 1955, Compound IV is obtained. However, the reactionproduct which is employed herein and which is described in the Grassettiapplication referred to above, is fundamentally different from CompoundIV. In other words, it is not merely a complex of Compound IV plus borontrifiuoride. This is borne out by the fact that one cannot extrapolatethe nitrogen content of the novel complex herein from the nitrogencontent of Compound IV. If Compound IV i treated with boron trifluoride,the aforementioned reaction product will not be obtained. Also, ifCompound IV is refluxed with water, no appreciable amount of vitamin Aaldehyde is obtained whereas the Grassetti application describes aprocess for obtaining vitamin A aldehyde by refluxing the above productwith water.

The following describes my novel procedure for obtaining vitamin Aaldehyde by treatment of the reaction product of Compound I and borontrifluoride hexamethylene tetramine complex with iodine. To thisreaction product there is added from 5% to 35% by weight of iodine basedon the weight of Compound I. The preferred ratio is from 20% to 25% byWeight of aeeaoeo iodine based on the weight of Compound I. The iodinecan be added to the reaction product of Compound I and boron trifluoridehexamethylene tetramine complex which has previously been isolated fromits reaction mix ture, e. g., by filtration of the spontaneouslyprecipitated reaction product complex or by adding excess hexamethylenetetramine to the reaction mixture and evaporating to dryness. It hasbeen found that the product is stabilized by the presence of excesshexamethylene tetramine. The isolated product may be dissolved insolvents such as those previously disclosed for carrying out thereaction between Compound I and the boron trifluoride hexarnethylenetetramine complex. Preferably the iodine is added to the reactionproduct which has not been isolatedbut which remains in situ in its ownreaction mixture, this reaction mixture serving as a solvent. If thereaction of Compound I and boron trifluoride hexamethylene tetramine iscarried out in a Water containing a solvent, additional amounts of watermay or may not be added to the reaction mixture on completion of thereaction before iodine is added. On the other hand, if no water ispresent in the. reaction mixture which contains the reaction product ofCompound I and boron trifluoride hexamethylene tetramine complex, or ifthis reaction product is isolated and is to be treated with iodine in awater free solvent then water should be added so that the Schiff base(imine) which is formed as a result of the action of iodine, ishydrolyzed to the aldehyde. Generally, this amount of water is about 15to 25 ml. per 100 ml. of total reactionvolume.

When carrying out the reaction with iodine, the reaction mixture isheated, preferably at the reflux temperature of this mixture containing,of course, the iodine, although a temperature range from 65 C. up toreflux temperature may be used. However, even upon standing at roomtemperature for several days, some aldehyde is obtained althoughaccompanied by relatively large amounts of polymeric material. Only ashort time is necessary for heating, usually from about fifteen minutesto one-half hour has been found to be ample to bring about the formationof vitaminA aldehyde.

Excess iodine is then eliminated from the reaction mixture by addingsodium thiosulfate thereto in an amount suflicie t to remove all of theiodine color. The vitamin A aldehyde is then readily recovered from thereaction mixture by any desired means. Extraction with a,water-immisciblesolvent such as hexane is preferred. This solvent is inturn removed by evaporation. In all cases a very excellent yield ofvitamin A aldehyde free of anhydro vitamin A is obtained. Thus thepresent invention is a further unexpected improvement over theaforementioned Grassetti application wherein subsequent treatment toremove anhydro vitamin A is required.

For a fuller understanding of the nature and objects of the invention,reference may be had to the following examples which are given merelyfor purposes of illustration and are not to be construed in a limitingsense:

Example I 120 mg. of the trans isomer of Compound I were dissolved in12.5 ml. of dioxane and the resulting solution added to a solution of229 mg. of a boron trifluoride hexamethylene tetramine complexcontaining 2 molecules of boron trifluoride for each molecule ofhexamethylene tetramine dissolved in 1.25 ml. of water. The reactionmixture was allowed to stand for half an hour at room temperature andthen 3.35 ml. of water were added thereto. Then 20 mg. of iodine wereincorporated in the reaction mixture and the reaction mixture refluxedfor half an hour ona steam bath. The reaction mixture was then cooledunder nitrogen and the iodine color was discharged from the reactionmixture using a aqueous solution of sodium thiosulfate. 50 ml. of hexanewere added to the reaction mixture and the product extracted into thehexane phase. The excess sodium toeliminate the aeetaldehyde that isformedduring such hydrolysis, before drying. The procedureemployedwasthat described in Experiments in Organic Chemistry, Fieser, 2nd edition,copyright 1941, D. C. Heath 8; C0., page 369.

Example, 11

0.240 gram. of the trans isomer of CompoundI was dissolved in 25 ml. ofdioxane. This dioxane was dis-.

tilled before use. Thereafter, the solution of dioxane containingCompound Idissolved therein was addedto a solution containing 0.458.gram of borontrifluoride hexamethylene tetramine complex. containing 2mole,- cules of boron. trifluoride for. each, moleculeof. hexamethylenetetramine dissolvedin 2.5 ml. of water. This addition was made at roomtemperature. Thereafter, the resulting mixture was allowed to stand forhalf an hour at room temperature. Then 6.7 ml; of -.water was added.

To one portion, equal to one-half of the above solution, 40 mg. ofiodine were added and the solution refluxed for half an hour.Thereafter, it was treated with hexane. and a 10% aqueous solutionofsodiumthiosulfate in order to remove the iodine present. Recovery ofthe product from the hexane extracts, gave. upontanalysis, a smooth,

continuous vitamin A aldehyde curvewith A. maxm3700 A. Thisspectographic curve also indicated that the.vitamin A aldehyde was freefromanhydro vitamin A. The net yield was.60.3%. If desired, further.purification can be effected, e g., by chromatography. Such was done inthis procedure over water deactivated alumina and a new A max=3800 A.was obtained.

To the remaining portion of the solution, 5 ml. of dioxane was added andthe solution then refluxed for onehalf hour. Thereafter, the reactionproduct. was extracted with hexane. A vitamin A aldehyde yield of 57.5%was obtained. However, it was contaminated with anhydro vitamin A to anamount of between 10 and 15%. Upon ultra-violet analysis, a broaderultra-violet curve, indicative of greater amounts of polymer formation,was observedas compared with the. curve obtained from the first portionwhich Was treated with iodine. Thus the yield of 57.5% vitamin Aaldehyde obtained from this second portion must be corrected for thepresence of anhydro vitamin A.

As all of the reactantsand products obtainedherein are susceptible toair oxidation, it is desirable to carry out all of the foregoingprocedures in the presence of an inert atmosphere suchas nitrogen,helium, etc. 7

Vitamin A aldehyde which is obtained by the present invention may beconverted to vitamin A by reduction with lithium aluminum hydride asdescribed byWendler et al. in J. Am. Chem. Soc. 72, 239 (1950).

As indicated by the foregoing, a novel process for obtaining vitamin Aaldehyde has been described. The product is obtained in high yields andfree from anhydro vitamin A, an undesirable material having no vitamin Aactivity. Thisabsence of anhydro is extremely surprising becauseCompound I contains an estimated 7 to 10% of anhydro vitamin A. Hence,this process is highly advantageous because it avoids costly and tediouschromatographic procedures for the removal of anhydro vitamin U. S.patent application Serial No. 679,519 of Grassetti filed concurrentlyherewith in order to obtain the vitamin.

A aldehyde in a highly pure form.

Moreover, if one desires to reduce vitamin A aldehyde .containinganhydro vitamin A to vitamin A alcohol with, e. g., lithium aluminumhydride and thereafter separate the anhydro by chromatography,inevitable losses of vitamin A alcohol result since more often than notsome of the vitamin A alcohol is transformed to anhydro vitamin A by theaction of the adsorbent. It is expected that this phenomenon will becomemore pronounced upon large scale chromatographic operations.

It seems apparent that the iodine is exhibiting selectivity ineliminating the anhydro and yet at the same time having no deleteriousefiect on the desired vitamin A aldehyde. The present process is anextremely advantageous one, not only because of the fact that a purerproduct in high yields is obtained, but because it employs a moreeconomical procedure. The reaction product of Compound I and borontrifluoride hexamethylene tetramine complex may be treated with iodinewithout being isolated from its reaction mixture. This procedureeliminates the usually necessary steps of working up the reactionproduct with alkaline materials and subsequent separation andpurification of the reaction product as done in the case of Compound IV.Thus, economies in time and in manipulative procedures are effectedsince there is no occasion to employ extra reagents such as alkalinematerials and organic solvents. The latter by necessity require safetyprecautions and in many instances require recovery procedures due totheir expense.

It will be appreciated that various modifications can be made in theinvention described above and such are within the scope of the presentinvention as defined in the appended claims.

Having described my invention What I claim is new and desire to secureby Letters Patent is:

1. A process for producing an imine intermediate which when reacted withwater yields anhydro free vitamin A aldehyde which comprises reactingwith iodine, a complex obtained by reacting at least one mole of a borontrifiuoride hexamethylene tetramine complex containing from about 1.5 to2.5 moles of boron trifluoride per mole of hexamethylene tetramine atbetween room temperature and 35 C. in the presence of a solvent with onemole of said complex having a x max=3300 A. and an 2. A process forproducing a vitamin A intermediate which comprises reacting with iodinein solution, a com plex obtained by reacting at least one mole of aboron trifluoride hexamethylene tetramine complex containing from about1.5 to 2.5 moles of boron trifluoride per mole of hexamethylenetetramine at between room temperature and 35 C. in the presence of asolvent with one mole of CH3 CI Q 3. A process forproducing a vitamin Aintermediate which comprises reacting in a solvent and at a temperatureof between 65 C. and the reflux temperature of the mixture, iodine and acomplex obtained by reacting at least one mole of a boron trifluoridehexamethylene tetra- E5 mine complex containing from about 1.5 to 2.5moles of boron trifluoride per mole of hexamethylene tetramine atbetween room temperature and 35 C. in the presence of a solvent with onemole of said complex having a )t max=3300 A. and an said iodine beingpresent in an amount of from 5 to 35% by weight of said 4. The processof claim 3 in which said solvent is selected from the group consistingof water-containing hydrocarbons, acetone, acetonitrile, acrylonitrile,benzyl cyanide, dioxane, isopropenyl acetate, tetrahydrofuran andmixtures thereof.

5. The process of claim 3 in which said iodine is present in an amountof between about 20 and 25%, based on the weight of said 6. A processfor producing anhydro free vitamin A aldehyde which comprises reactingin solution at a temperature of between 65 C. and the reflux temperatureof the mixture and in the presence of a small amount of water, iodineand a complex obtained by' reacting at least one mole of a borontrifluoride hexamethylene tetramine complex containing from about 1.5 to2.5 moles of boron trifluoride per mole of hexamethylene tetramine atbetween room temperature and 35 C. in the presence of a solvent with onemole of said complex having a A max=3300 A. and an said iodine beingpresent in an amount of from 5 to 35% by weight of said 7. A process forproducing anhydro free vitamin A aldehyde which comprises adding iodineto a complex in situ in its original reaction mixture which acts as asolvent for said reactants while having present water and heating at atemperature between 65 C. and the reflux temperature of the mixture,said complex being obtained by re- CH3 CH3 V CH3 CH3 said complex havinga A max=3300 A. and an said iodine being present in an amount of from 5to 35% by weight of said 8. The process of claim 7 wherein said solventcomprises dioxane and water. a

9. The process of claim 7 in which there is present from about to 25 ml.of Water per 100 ml. of total reaction volume.

10. The process of claim 7 in which said iodine is present in an amountof from about and based on the weight of said No references cited.

1. A PROCESS FOR PRODUCING AN IMINE INTERMEDIATE WHICH WHEN REACTED WITHWATER YIELDS ANHYDRO FREE VITAMIN A ALDEHYDE WHICH COMPRISES REACTINGWITH IODINE, A COMPLEX OBTAINED BY REACTING AT LEAST ONE MOLE OF A BORONTRIFLUORIDE HEXAMETHYLENE TETRAMINE COMPLEX CONTAINING FROM ABOUT 1.5 TO2.5 MOLES OF BORON TRIFLUORIDE PER MOLE OF HEXAMETHYLENE TETRAMINE ATBETWEEN ROOM TEMPERATURE AND 35*C. IN THE PRESENCE OF A SOLVENT WITH ONEMOLE OF
 6. A PROCESS FOR PRODUCING ANHYDRO FREE VITAMIN A ALDEHYDE WHICHCOMPRISES REACTING IN SOLUTION AT A TEMPERATURE OF BETWEEN 65*C. AND THEREFLUX TEMPERATURE OF THE MIXTURE AND IN THE PRESENCE OF A SMALL AMOUNTOF WATER, IODINE AND A COMPLEX OBTAINED BY REACTING AT LEAST ONE MOLE OFBORON TRIFLUORIDE HEXAMETHYLENE TETRAMINE COMPLEX CONTAINING FROM ABOUT1.3 TO 2.5 MOLES OF BORON TRIFLUORIDE PER MOLE OF HEXAMETHYLENETETRAMINE AT BETWEEN ROOM TEMPERATURE AND 35*C. IN THE PRESENCE OF ASOLVENT WITH ONE MOLE OF